Family History Influences AD Biomarker Abnormalities

A family history (FH) of Alzheimer’s disease (AD) is linked to preclinical abnormalities in disease biomarkers, independent of the risk conferred by the apolipoprotein E (APOE) susceptibility gene in cognitively normal middle- to older-aged individuals [Arch Neurol. 2011;68(10):1311-1317]. Researchers from Washington University School of Medicine conducted a study of 269 cognitively normal patients, aged 45 to 75 years, who were part of the Antecedent Biomarkers for AD: The Adult Children Study (ACS) to determine whether FH alone conveys AD risk beyond that of APOE4 by examining the influence of FH for AD, both together and independent of APOE4, on biomarker abnormalities using the baseline data of the ACS. Individuals with and without an FH of AD were included in the study. A positive FH for AD was defined as having at least 1 biological parent with age onset for dementia of the Alzheimer type (DAT) <80 years; a negative FH was defined as both biological parents living to ≥70 years of age without DAT. Eligibility criteria for study inclusion included ages 45 to 75 years, availability of an individual who knew the patient well, normal cognition, and a willingness in principle to complete all procedures. All patients completed baseline clinical and psychometric assessments. Of the cohort, 217 (80.7%) had a lumbar puncture to obtain cerebrospinal fluid (CSF), 206 (76.6%) completed positron emission tomography (PET), using the [11C] benzothiazole tracer, Pittsburgh compound B (PIB), 147 (54.6%) underwent magnetic resonance imaging (MRI), and 232 (86.2%) completed attentional tasks. Overall, 108 (40.1%) completed all baseline procedures. Primary end points included clinical and cognitive measures, MRI-based brain volumes, diffusion tensor imaging-based white matter microstructure, CSF biomarkers, and molecular imaging of cerebral fibrillar amyloid with PET PIB. This study found that the mean level of CSF Aβ42 decreased significantly with age at a rate of −7.76 (2.14) pg/mL per year (P<.001) in patients with a positive FH but not in those without (P=.35). The presence of APOE4 allele did not alter the effect of FH on age-related decrease in CSF Aβ42 (P=.50). Those with APOE4 had lower levels of age-adjusted CSF Aβ42, compared with the corresponding level in those without (P<.001), and the reduction was greater if FH was positive, compared with the decrease if FH was negative (F1,209=5.29; P=.02). Although no significant effect on FH or APOE4 was observed for CSF tau in age-related rate of change, patients with a positive FH had a higher level of CSF tau than those otherwise aged ≥55 years (F1,152=4.60; P=.03). For patients <55 years of age, mean cortical binding potential (MCPB) increased by age at a considerably faster pace for patients with APOE4, compared with the pace for those without APOE4 (F1,62.4=4.72; P=.03), eventually leading to a higher level of MCPB for patients with APOE4 compared with the level for those without (P=.01). For those >55 years of age, a trend (P=.09) was found to suggest a faster age-related increase of MCPB for those with APOE4 compared with the increase for those without APOE4. Patients positive for both FH and APOE4 had the largest age-related increase of MCBP (P<.001). Furthermore, a positive FH was associated with decreased fractional anisotropy from diffusion tensor imaging in the genu (F1,142=3.91; P=.05) and splenium (F1,142=4.12; P=.04) of the corpus callosum. “The current results point to the likelihood of non-APOE susceptibility genes for AD.” Together, the data “suggest that AD has a lengthy period during which cerebral lesions gradually accumulate in the absence of symptoms (ie, preclinical AD). We expect that eventually these lesions cause sufficient synaptic and neuronal damage to result in symptomatic AD,” concluded the researchers. Study limitations included that ACS is an observational study on a convenience sample. The lack of longitudinal data on biomarkers prevented the researchers from understanding the cascade of early events in AD pathogenesis.